It has been the dogmatic belief that cells infected with cytopathic virus - such as influenza A virus (IAV) - will either undergo cell death or will be removed by the immune system. Cells that survive viral infection have been difficult to study because, once infection has been cleared, these cells are indistinguishable from cells that have never encountered a virus. However, cellular populations that survive cytopathic viral infection exist and, until recently, have been unstudied. The Palese laboratory has identified a cellular population that, while susceptible and permissive to IAV, is capable of successfully eliminating the pathogen and surviving infection. This has led to the identification of club cells (formerly known as Clara cells) as one population that survives IAV infection in vivo. I have expanded upon this work and established an in vitro system that utilizes club cells as a model for cellular survival of influenza A virus infection. I have generated a tissue culture club cell line that permanently expresses a fluorescent protein upon infection with an IAV that expresses Cre recombinase (IAV- Cre). These transgenic club cells become fluorescent both during infection and after viral clearance. In this way, club cells surviving IAV infection are labeled allowing ther identification and study. The major objective of this fellowship application is to identify the fundamental cell-intrinsic factors and pathways that enable cells to eliminate viral infection without undergoing cell death. By using a comprehensive RNAi approach, I will screen for factors that allow for this survival phenotype in a reductionist manner. Moreover, I will determine how surviving IAV infection alters the physiology of club cells. This proposal intends to elucidate the cell-intrinsic defenses that have evolved in club cells to fight IAV infection on a cell-by-cel basis; this knowledge has broad implications for understanding new aspects of influenza-related disease. Additionally, research into this novel area of antiviral cell biology has the potential to explain a mechanism of immunity that may be broadly applicable to other types of viral infections.